It is a fundamental requirement for biological cells to sense and respond to mechanical stress. In the heart, high peripheral resistance (high blood pressure, pressure-overload) is countered by increasing contractility of the myocardium, known as the Anrep effect; enlarged diastolic volume (volume overload) is also countered by increasing contractility, known as the Frank-Starling mechanism. While the heart senses mechanical stress and adjusts contractility to meet varying hemodynamic needs, excessive strain and stress (pressure-overload, volume-overload) also lead to cardiac dysfunction and heart disease development. The mechanical integrity of a cardiac myocyte is maintained by a network of structural proteins including the costamere (elaborated version of focal adhesion complex) that encircles the z-disks to provide structural support (FIG. 1). The costamere comprises the dystrophin-glycoprotein complex (DGC) and the vinculin-talin-integrin complex (VTI). The importance of these mechanical stress bearing and sensing proteins are demonstrated in various Muscular Dystrophy, in which mutations in DGC or VTI lead to cardiac dysfunction and dilated cardiomyopathy. Although these phenomena are well known for over a century, the cellular and molecular mechanisms that transduce mechanical strain and stress to intracellular biochemical reactions, so called mechano-chemo-transduction (MCT) mechanism, remains poorly understood to date. As result, effective therapies are still lacking for treating mechanical stress-induced heart diseases such as Muscular Dystrophy Cardiomyopathy and Hypertension induced Cardiac Arrhythmias and Heart Failure.